2. Academic Validation
  3. Systematic interrogation of functional genes underlying cholesterol and lipid homeostasis

Systematic interrogation of functional genes underlying cholesterol and lipid homeostasis

  • Genome Biol. 2025 Mar 17;26(1):59. doi: 10.1186/s13059-025-03531-8.
Haihuan Shan 1 2 3,  Shuangshuang Fan 1 2 3,  Quanrun Li 1 2 3,  Ruipu Liang 1 2 3,  Zhisong Chen 1 2 3,  Shengnan Wang 1 2 3,  Xiaofeng Wang 1 2 3,  Yurong Li 1 2 3,  Shuai Chen 4,  Kun Yu 5,  Teng Fei 6 7 8
Affiliations

Affiliations

  • 1 Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, 110819, China.
  • 2 National Frontiers Science Center for Industrial Intelligence and Systems Optimization, Northeastern University, Shenyang, 110819, China.
  • 3 Key Laboratory of Data Analytics and Optimization for Smart Industry (Northeastern University), Ministry of Education, Shenyang, 110819, China.
  • 4 Research Center for Analytical Sciences, Department of Chemistry, College of Sciences, Northeastern University, Shenyang, 110819, China.
  • 5 College of Medicine and Bioinformation Engineering, Northeastern University, Shenyang, 110819, China.
  • 6 Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, 110819, China. [email protected].
  • 7 National Frontiers Science Center for Industrial Intelligence and Systems Optimization, Northeastern University, Shenyang, 110819, China. [email protected].
  • 8 Key Laboratory of Data Analytics and Optimization for Smart Industry (Northeastern University), Ministry of Education, Shenyang, 110819, China. [email protected].
PMID: 40098013 DOI: 10.1186/s13059-025-03531-8
Abstract

Background: Dyslipidemia or hypercholesterolemia are among the main risk factors for cardiovascular diseases. Unraveling the molecular basis of lipid or Cholesterol homeostasis would help to identify novel drug targets and develop effective therapeutics.

Results: Here, we adopt a systematic approach to catalog the genes underlying lipid and Cholesterol homeostasis by combinatorial use of high-throughput CRISPR screening, RNA Sequencing, human genetic variant association analysis, and proteomic and metabolomic profiling. Such integrative multi-omics efforts identify gamma-glutamyltransferase GGT7 as an intriguing potential Cholesterol and lipid regulator. As a SREBP2-dependent target, GGT7 positively regulates cellular Cholesterol levels and affects the expression of several Cholesterol metabolism genes. Furthermore, GGT7 interacts with actin-dependent motor protein MYH10 to control low-density lipoprotein Cholesterol (LDL-C) uptake into the cells. Genetic ablation of Ggt7 in mice leads to reduced serum Cholesterol levels, supporting an in vivo role of Ggt7 during Cholesterol homeostasis.

Conclusions: Our study not only provides a repertoire of lipid or Cholesterol regulatory genes from multiple angles but also reveals a causal link between a gamma-glutamyltransferase and Cholesterol metabolism.

Keywords

CRISPR; Cholesterol; GGT7; Gamma-glutamyltransferase; Lipid.

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